Gall, et al., U.S. Pat. No. 3,842,090 discloses a multi-step process for preparing 1-aminomethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines, e.g., adinazolam, from 2-(unsubstituted triazolyl)benzophenones. However, for larger scale production the use of multi-step processes and time consuming column chromatography are disadvantages, which those in the art seek to avoid.
Gall, U.S. Pat. No. 4,001,262 discloses a process for preparing 1-[(dimethylamino)methyl]-6-substituted 4H-s-triazolo[4,3-a][1,4]benzodiazepines, e.g., adinazolam, by reacting a 4H-s-triazolo[4,3-a][1,4]benzodiazepine, e.g., estazolam, with a dimethyl(methylene)ammonium halide salt reagent in one step. However, that patent also reports the use of chromatography procedures in the detailed examples thereof for purifying the end product thereof.
Derwent Abstract 48681A briefs a Japanese Patent Publication No. 59696/78, published May 29, 1978, disclosing the ring closure of 2',5-dichloro-2-[3-(dimethylaminomethyl)-5-mesyloxymethyl-4H-1,2,4-triazol -4-yl]benzophenone in a sealed tube with ammonia containing methanol to obtain 8-chloro-6-(2-chlorophenyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a] [1,4]benzodiazepine. However, sealed tube procedures are not practical for commercial scale chemical process operations, and the abstract does not disclose how the (3-hydroxymethyl-triazol-4-yl)-compounds are obtained.
Derwent Abstract 52339T describes a West German patent application No. 2201210 published Aug. 3, 1972 and disclosing the conversion of 1-hydroxyalkyl-triazolobenzodiazepines via a reactive ester to the corresponding 1-[(dimethylamino)methyl]triazolobenzodiazepines.
Those in the art continue to search for improved methods for making valuable drug compounds more efficiently.